We propose to establish a Biomedical Technology Research Center (BTRC) in High Performance Computing for Multiscale Modeling of Biological Systems, as a joint effort between the U of Pittsburgh (Pitt; lead institution), Carnegie Mellon U (CMU), the Pittsburgh Supercomputing Center (PSC) and Salk Institute. The Center will develop technology and tools to facilitate research and training at the interface between computing technology and life sciences, and focus on a deeper understanding ofthe molecular and cellular organization and mechanisms that underlie synaptic signaling and regulation, thus facilitating the discovery of new treatments against nervous system disorders. The goal is to start filling the gap between modeling efforts at disparate scales of structural biology, cellular microphysiology and large scale image analysis. Computational technology research and development (TR&D) studies will be conducted in (i) molecular modeling and simulations, (ii) cell modeling and simulations, and (iii) bioimage processing and analysis. These activities will emphasize developing tools to tackle the spatial and molecular complexity inherent in signal transmission and will be driven by five experimental driving biomedical projects (at Pitt, Caltech, Harvard and UT Southwestern Medical Center) on (i) neurotransmitter transport by excitatory amino acid transporters, (ii) activation of CaMKII in spines, (iii) dopamine transporter trafficking in dopamie neurons, (iv) Itk as a regulator of T cell signaling, and (iv) neuronal circuit reconstruction from serial section transmission electron microscopy images. The Center will carry out a vigorous training and dissemination program in its areas of concentration, it will leverage the capabilities of the PSC which has been home to a BTRC for more than twenty years and, besides its biomedical technology research, has a long track record of service, training and dissemination. It will also take advantage ofthe unique strengths ofthe Computational & Systems Biology Department at Pitt, and the Lane Center for Computational Biology at CMU, building on numerous successful collaborative research and training efforts between the two universities, and cutting-edge research at the Computational Neurobiology Laboratory at the Salk Institute.